Glycan deletions in the HIV-1 gp120 V1/V2 domain compromise viral infectivity, sensitize the mutant virus strains to carbohydrate-binding agents and represent a specific target for therapeutic intervention.
Carbohydrate-binding agents (CBAs), such as the mannose-specific Hippeastrum hybrid agglutinin (HHA) and the GlcNAc-specific Urtica dioica agglutinin (UDA), frequently select for glycan deletions in all different domains of HIV-1 gp120, except in the V1/V2 domain. To reveal the underlying mechanisms, a broad variety of 31 different virus strains containing one or several N-glycan deletions in V1/V2 of the gp120 of the X4-tropic HIV-1(NL4.3) were constructed by chimeric virus technology. No co-receptor switch to CCR5 was observed for any of the replication-competent mutant virus strains. With a few exceptions, the more glycans were deleted in the gp120 V1/V2 domain, the more the replication capacity of the mutant viruses became compromised. None of the mutant virus strains showed a markedly decreased sensitivity to the inhibitory activity of HHA and UDA. Instead, an up to 2- to 10-fold higher sensitivity to the inhibitory activity of these CBAs was observed. Our data may provide an explanation why glycan deletions in the gp120 V1/V2 domain rarely occur under CBA pressure and confirm the important functional role of the glycans in the HIV-1 gp120 V1/V2 domain. The gp120 V1/V2 loop glycans of HIV-1 should therefore be considered as a hot spot and novel target for specific therapeutic drug intervention.
Auwerx
Joeri
J
Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
François
Katrien O
KO
Covens
Kris
K
Van Laethem
Kristel
K
Balzarini
Jan
J
D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000737:chemistry* / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D020128:Inhibitory Concentration 50; D037102:Lectins / Q000378:metabolism / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D016297:Mutagenesis, Site-Directed; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D011485:Protein Binding; D014779:Virus Replication
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D037102:Lectins; D050505:Mutant Proteins; C514793:gp120 protein, Human immunodeficiency virus 1